Synthesis and in vitro antitumor activity of substituted anthracene-1,4-diones

Based on a rational approach, 6-substituted 1,4-anthracenediones were synthesized and found to exhibit potent cytotoxic activity against murine and human leukemic cells. The synthetic sequence includes a double Friedel-Crafts reaction, reductive quinone formation, and selective bromination of the alkyl side chain. A key intermediate, 6-bromomethyl-1,4-anthracenedione (10), was synthesized and converted to various active antitumor agents, including a water-soluble phosphate ester pro-drug. The interconversion reactions include displacement of the bromide with various nucleophiles and basic hydrolysis to the alcohol and subsequent oxidation to provide the aldehyde. Based on their ability to decrease L1210 and HL-60 tumor cell viability, 1,4-dihydroxyanthraquinones are inactive but 1,4-anthracenediones have interesting antitumor activity, which may be abolished by modification of the A-ring and improved by substitution of the C-ring. The cytostatic and cytotoxic activity of the representative compound 10 was verified at the National Cancer Institute in studies on the 60-human tumor cell line panel in the in vitro antitumor screening. A wide spectrum of tumor cells are sensitive to 10 inhibition, and concentrations required to inhibit tumor cell growth by 50% (GI₅₀) at 48 h are <10 nM in HL-60 and MOLT-4 and 37.1 nM in SR leukemia. Preliminary studies suggest that the molecular targets and mechanisms of action of 10 may be different from those of daunomycin.     

槲皮素苯磺酸酯前药的设计与合成

为了提高槲皮素的生物利用度以改善其抗肿瘤等活性,本论文根据其体内基本传递特性,利用前药原理成功设计合成了3个新型槲皮素磺酸酯衍生物(1,3～4),所有化合物的结构均经IR,MS,元素分析和1H NMR等确证.对目标产物进行溶解度测定,发现三种目标化合物的脂溶性与水溶性均有显著的提高.     

生物正交剪切反应及其应用

生物正交反应在化学生物学的研究中发挥着越来越重要的作用.传统的生物正交反应以新化学键生成的连接反应为主,其在实现生物分子的“标记”、“示踪”和“捕捉”等研究中发挥着重要作用.近年来,一类新兴的反应类型--以化学键断裂为基础的生物正交剪切反应逐渐发展起来,并在分子的“释放”、“激活”和“操控”等方面得到了越来越广泛的应用.本文首先重点介绍了生物正交剪切反应,总结了这些反应的特点、适用范围和已经实现的用途.随后通过具体的例子介绍了这些反应在化学生物学中的应用,包括小分子前药的激活、蛋白质功能的调控、细胞的工程化等.最后文章对生物正交剪切反应的发展趋势进行了展望.     

恩替卡韦钠的核磁共振谱分析

对恩替卡韦钠进行了¹H和¹³C NMR检测,通过DEPT和¹H-¹H COSY、HMQC、HMBC等2D NMR技术对该化合物所有的¹H和¹³C NMR信号进行了全归属,并通过NOESY确证了其相对立体结构.     

Total Syntheses of a 16a'-Homoleurosidine and a 16a'-Homovinblastine

Vinblastine has been used in clinic as an anti-cancer agent. Due to its high cytotoxity, generation of vinblastine congeners as safe anti-cancer agents is always the interesting topic in medicinal chemistry. In the previous synthesis of vinblastine, it has been found that a higher energy conformation of vinblastine lacking cytotoxity and inhibition against tubulin polymerization, can be converted to its lower energy natural conformation on heating to 110 ℃. The high temperature (110 ℃) other than a physiological temperature required for the conformational inversion excludes the possibility of using the higher energy conformational isomer as a potential pro-drug for thermal activation. In the continuing of searching for thermal activated anti-cancer pro-drug, we re-designed and synthesized new vinblastine congeners with the enlarged azonine ring by inserting one carbon atom at the C-16 position of azonine ring in order to decrease the energy barrier for the conformational inversion.In this paper, we wish to report the total syntheses of 16a'-homoleurosidine and 16a'-homovinblastine, the azonine ring expanded compounds of vinblastine and leurosidine respectively. The synthesis of 16a'-homoleurosidine was achieved through enatioselective generation of a tetracyclic intermediate by a Diels-Alder reaction, followed by ring expansion of the tetracyclic intermediate by regioselective rapture of a cyclopropane ring as key steps. The synthesis of 16a'-homovinblastine was achieved through stereoselective inversion of the tertiary hydroxyl group from R configuration to the S configuration in the tetracyclic intermediate. The 16a'-homoleurosidine was obtained dominantly in its high energy conformation at room temperature and neutral condition. On protonation, a 1:1 mixture of atropisomers of 16a'-homoleurosidine was found. In contrast to 16a'-homoleurosidine, the 16a'-homovinblastine existed in the form of two atropisomers in a 1:2.3 ratio at room temperature and neutral condition, with a complete shift to the lower energy atropisomer with increasing solvent acidity. The hydrogen bond formed between the nitrogen atom and the hydroxyl group of piperidine ring played a key role in controlling the equilibrium shift between the higher energy atropisomer and the lower energy atropisomer.     

One-Pot Synthesis of 5′-Diaryl Esters and Diamidates of Phosphate,Phosphorothioate, and Phosphoroselenoate Derivatives of AZT and d4T

Modified nucleosides such as 3′-azido-2′,3′-dideoxythymide (AZT) and 2′,3′-dideoxy-2′,3′-didehydrothymide (d4T) are of importance as antiviral agents and in other medicinal applications. Consequently, there is interest in new analogs of these compounds and in new methods for preparing them. In this article, a simple but efficient, one-pot synthesis of 5′-diaryl esters and diamidates of phosphate, phosphorothioate, and phosphoroselenoate derivatives of AZT and d4T is described. The reaction of AZT/d4T with phosphorus trichloride, followed with phenols, aniline, or amino acid methyl esters in the presence of a base, led to the corresponding tricoordinated phosphite compounds of AZT/d4T, which were then oxidized with 3-chloroperoxybenzoic acid (m-CPBA), sulfur, or selenium powder to finally afford the corresponding target compounds in good yield.     

CPS LG 313 Phenylalkanol — adsorbates on silica as types of immobilized drugs 1. Chemiadsorption on activated silica surfaces

The chemiadsorption of phenylalkanols onto a porous silica support (d _pore 10 nm) viaSi-O-C bonds was studied. The silica support was activated prior to the alcohol adsorption by annealing or by the introduction ofSi-Cl groups. Different reaction conditions were applied, namely time, temperature, solvent and drug-support ratio. The yield of chemiadsorption was dependent on both the reaction conditions and the structure of the alcohols. Long alkyl chains, especially those with an alcohol OH-group positioned in the vicinity of bulky substituents, reduce the yield considerably. Using chlorinated silica, a reasonable yield of chemiadsorption can be obtained even at relatively low reaction temperatures.Dedicated to Professor Dr. Dr. h. c. Armin Weiss on the occassion of his 60th birthday.